The molecular events leading to putuitary thyrotroph cell division with eventual neoplastic transition will be studied in rats and mice during acute and chronic hypothyroidism. The decrease in L-triiodothyronine (T3) concentration in hypothyroidism results in the desaturation of the nuclear T3 receptor which is a chromatin nonhistone protein and causes an increase in cell function (TSH secretion) and rate of cell division. Since this class of chromatin proteins plays a critical role in activation of the genome in all phases of the cell cycle, it is likely that changes in these nuclear proteins during hypothyroidism lead to an altered thyrotroph cell cycle resulting in hyperplasia and neoplasia. The proposed studies will first explore the cell cycle of the normal thyrotroph, the distribution of the nuclear T3 receptors among different cell lines in the anterior pituitary and the time of onset of thyrotroph cell division in the rat. The baseline information obtained from these studies will then be used to determine: a) alterations in the physico-chemical characteristics of the nuclear T3 receptor; b) the regulation of TSH secretion by T3 and thyrotrophin releasing hormone (TRH); and c) nonhistone chromatin protein patterns, synthesis, turnover, and phosphorylation in different stages of thyrotroph transition from normal cells to undifferentiated metastasizing neoplasms. Parameters (a), (b) and (c) will be studied in normal thyrotrophs, at the onset of thryrotroph hyperplasia, and in transplanted hormone-dependent thyrotrophic tumors. These studies should lead to a well characterized model system which should provide new insights into the interrelationships between the chromatin protein T3 receptors, cell function, chromatin protein metabolism, and cell replication. The studies should, in addition, clearly define the nature and regulation of nonsuppressible TSH secreted by the thyrotrophs as well as the kinetics of thyrotroph and somatotroph replication.